Closed head traumatic brain injury (CH-TBI) results in a broad spectrum of neurological deficits. Recently, those involving cognition, pain sensitivity, and anxiety, have risen to the level of urgency for the development of new information that can enhance therapy for CH-TBI. This study proposes a unifying hypothesis regarding the multiple-morbidity that frequently following CH-TBI. It proposes that that dysfunction of the central noradrenergic (NA) system is a common underlying denominator of these multiple disabilities. Four aims are proposed to investigate specific neurological deficits induced by CH-TBI, how these are correlated with noradrenergic injury, and the potential for these deficits to be modified by three treatments that target upregulation of the central noradrenergic system. A fifth aim proposes a proof of principle sudy. Aim 1 will determine the severity and time-course of the three neurological manifestations following mild/moderate CH-TBI in a rat head injury model. Aims 2 will correlate the magnitude of behavioral changes after CH-TBI with measures of NA expression in regions of the brain predominantly involved in the specific behaviors of interest (i.e., hippocampus CA1 and CA3, central nucleus of the amygdala, and cervical and lumbar dorsal spinal gray matter). The third Aim will test the safety, feasibility, and efficacy of three therapies - activity wheel locomotor (AWL) exercise, transcortical magnetic stimulation (TMS), and pregabalin alone or in combination - on cognitive, pain, and anxiety outcomes of mild and moderate CH-TBI. Aim 4 will examine how these treatments affect regional NA expression using mass spectrometry and norepinephrine (NE) immunocytochemistry. Aim 5 will further test the central hypothesis by evaluating treatment efficacy (using the best treatment combination) in animals following selective immune-lesion of central noradrenergic neurons. The proposed studies will increase our knowledge base of: 1) CH-TBI-induced cognitive dysfunctions, anxiety, pain disabilities, and chronic inflammation; 2) the relationship of these disabilities with dysregulation of the central NA system; 3) the value of specific treatments to decrease the severity of long term disabilities; and 4) the impact of therapeutic program to significantly alter central NA levels and decrease the magnitude of CH-TBI-induced chronic inflammation. Translation of these findings may provide safe, timely, and effective intervention strategies which can significantly benefit the veterans' health care system.